Compositions and methods for treating cancer

ABSTRACT

The present invention is bis-acridine or bis-quinoline intercalators having a modified bis(4-aminophenyl)ether tether to improve activity, selectivity, solubility and bioavailability of the antitumor compound.

INTRODUCTION

This application claims the benefit of priority of U.S. application Ser.No. 13/236,969 filed Sep. 20, 2011, the content of which is incorporatedherein by reference in its entirety.

BACKGROUND OF THE INVENTION

Intercalation is one of several modes by which drugs interact with DNAwherein a planar portion of the drug is inserted in between adjacentstacked base pairs of a double stranded DNA. The intercalation processresults in helix extension and unwinding of the DNA. Included withinthese drugs are antitumor agents, actinomycin D, adriamycin anddaunomycin, as well as several drugs for treatment of parasitic diseaseincluding ethidium bromide, quinacrine, chloroquine and miracil D. U.S.Pat. No. 2,441,665 discloses a class of alkylene diamine derivativeswhich are valuable as antimalarial agents. U.S. Pat. No. 2,113,357discloses substituted amino-acridine derivatives useful in treatingblood parasites.

DNA intercalating ligands have also been shown to be useful in targetingalkylating agents to DNA by attachment of the intercalating ligand tothe alkylating agent (Gourdie, et al. (1991) J. Med. Chem. 34:240-248).Since the biological properties of these DNA intercalating drugs arebelieved to result from their binding, research efforts have focused ondesigning molecules that have a high affinity for DNA. Planar polycyclicaromatic molecules show a strong propensity to bind to DNA byintercalation (Jaycox, et al. (1987) J. Heterocyclic Chem. 24:1405-1408;U.S. Pat. No. 6,187,787). In this respect, efforts to identify moleculeswith a greater affinity and selectivity for DNA have resulted in thedevelopment of bifunctional intercalating agents in which twointercalating ligands are bridged by a central linking chain. Ingeneral, enhanced binding is observed with molecules of this type(Canellakis, et al. (1976) Biochim. Biophys. Acta 418:277; Becker &Dervan (1979) J. Am. Chem. Soc. 101:3664; Wakelin, et al. (1986) Med.Res. Rev. 6:275).

A homologous series of bisacridines containing two 9-aminoacridinechromophores linked via a simple methylene chain has been studied toinvestigate the minimum interchromophore separation required to permitbifunctional intercalation (Wakelin, et al. (1978) Biochemistry17:5057). Viscometric, sedimentation and electric dichroism experimentsshowed that compounds having one to four methylene groups in the linkerare restricted to monofunctional intercalation whereas bifunctionalinteraction was observed when the chain length was increased to sixmethylene groups or more.

Additional studies indicate that the nature of the bridging chain and/orsubstituents on the acridine ring has a profound effect on the abilityof bisacridine compounds to act as bifunctional intercalating agents.DNA binding characteristics of a number of acridine dimers of which twoaromatic rings, each ring being the monomeric2-methoxy-6-chloro-9-(3-dimethyl amino propylamino acridine), werelinked by a chain of varying length and structure were also determined(Le Pecq, et al. (1975) Proc. Nat'l Acad. Sci. USA 72(8):2915-2919). Thelinking chains of these acridine dimers included—(CH₂)₃—NH—(CH₂)₄—NH—(CH₂)₃—; —(CH₂)₃—NH—(CH₂)₄—; and—(CH₂)₃—NH—(CH₂)₃—. It was found that the two dimers with the longestchain length bis-intercalated, while only one of the two rings of thedimer with the shortest chain was intercalated. In contrast,bis-intercalators bridged by flexible chains have generally exhibitedreduced affinities for DNA, in part because of self-stackinginteractions, which compete with the binding process (Barbet, et al.(1976) Biochemistry 15:2642; Capelle, et al. (1979) Biochemistry18:3354). Further, bis-intercalation can introduce undesirable entropiceffects when a flexible linker is forced into an extended chainconformation (Jaycox et al. (1987) supra). In addition, it is a concernthat flexible bis-intercalators can creep in a step-wise fashion alongthe DNA macromolecule, thereby lowering ligand residence lifetimes atany one site (Denny, et al. (1985) J. Med. Chem. 28:1568). Such aprocess could have significant effects on efficacy of theseintercalators as anticancer agents as residence lifetimes have beencorrelated with in vivo antitumor activity for a large number of DNAintercalators (Feigon, et al. (1984) J. Med. Chem. 27:450).

SUMMARY OF THE INVENTION

The present invention features a compound of Formula I, or apharmaceutically acceptable salt and solvate thereof,

wherein dashed lines represent bonds that are independently present orabsent; and each R is independently an amide, amino, azido, nitro,hydroxyl, hydroxymethyl, carboxyl, cyano, sulfinyl, aryl, heteroaryl,alkenyl, alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycle,spirocycle, alkoxy, or halo group.

Pharmaceutical compositions and methods of inhibiting cancer cell growthand treating cancer in a subject using a compound of the invention arealso provided.

DETAILED DESCRIPTION OF THE INVENTION

The present invention features anti-cancer compounds, pharmaceuticalcompositions and methods for decreasing tumor cell proliferation,increasing survival, and treating cancer. Specifically, bis-acridine orbis-quinoline intercalators having a modified bis(4-aminophenyl)ethertether have now been developed to improve activity, selectivity,solubility and bioavailability of the antitumor compound. Compounds ofthe invention find application in decreasing cancer cell proliferationthereby making them useful in the treatment of cancer.

Compounds of the present invention are represented by Formula I:

and include pharmaceutically acceptable salts and solvates thereof. Inaccordance with Formula I, dashed lines represent bonds (A-E) that areindependently present or absent; and R is a group that improves one ormore of the pharmacological properties of the drug, e.g., solubility,permeability, bioavailability, stability, pKa, lipophilicity, bloodbrain barrier penetration, excretion, absorption, distribution,metabolism, transport, clearance, half-life, etc. In certainembodiments, R is an ionizable group, polar group or group capable ofparticipating in H-bonding. In particular embodiments, each R isindependently an amide (—CONH₂), amino (—NH₂), azido (—N₃), nitro(—NO₂), hydroxyl (—OH), hydroxymethyl (—CH₂OH), carboxyl (—CO₂H), cyano(—C≡N), sulfinyl (—SO), aryl, heteroaryl, alkenyl, alkyl, alkylene,cycloalkyl, cycloalkenyl, heterocycle, spirocycle, alkoxy, or halo (—Br,—F, —Cl, —I) group.

As used herein, the term “aryl” refers to an optionally substitutedbenzene ring or to an optionally substituted fused benzene ring system,for example anthracene, phenanthrene, or naphthalene ring systems.Multiple degrees of substitution are included within the presentdefinition. Examples of “aryl” groups include, but are not limited to,phenyl, 2-naphthyl, 1-naphthyl, and the like, as well as substitutedderivatives thereof.

As used herein, the term “heteroaryl” refers to an optionallysubstituted monocyclic five to seven membered aromatic ring, or to anoptionally substituted fused bicyclic aromatic ring system comprisingtwo of such aromatic rings. These heteroaryl rings contain one or moreheteroatoms such as nitrogen, sulfur, and/or oxygen atoms, whereN-oxides, sulfur oxides, and dioxides are permissible heteroatomsubstitutions. Multiple degrees of substitution are included within thepresent definition. Examples of “heteroaryl” groups used herein include,but should not be limited to, furan, thiophene, pyrrole, imidazole,pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole,thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine,quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole,benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl,pyrazolopyrimidinyl, and the like, as well as substituted versionsthereof.

As used herein, the term “alkenyl” refers to a straight or branchedchain aliphatic hydrocarbon containing one or more carbon-to-carbondouble bonds that may be optionally substituted, with multiple degreesof substitution included within the present invention. Examples include,but are not limited to, vinyl, allyl, and the like, as well assubstituted versions thereof.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon, preferably having from one to twelve carbon atoms, whichmay be optionally substituted, with multiple degrees of substitutionincluded within the present invention. Examples of “alkyl” as usedherein include, but are not limited to, methyl, ethyl, propyl,isopropyl, isobutyl, n-butyl, isopentyl, n-pentyl, and the like, as wellas substituted versions thereof.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical, preferably having from one to tencarbon atoms. Alkylene groups as defined herein may optionally besubstituted, with multiple degrees of substitution included within thepresent invention. Examples of “alkylene” as used herein include, butare not limited to, methylene, ethylene, n-propylene, n-butylene, andthe like, as well as substituted versions thereof.

As used herein, the term “cycloalkyl” refers to an optionallysubstituted non-aromatic cyclic hydrocarbon ring, which optionallyincludes an alkylene linker through which the cycloalkyl may beattached, with multiple degrees of substitution included within thepresent invention. Exemplary “cycloalkyl” groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and the like, as well as substituted versions thereof. Asused herein, the term “cycloalkyl” includes an optionally substitutedfused polycyclic hydrocarbon saturated ring and aromatic ring system,namely polycyclic hydrocarbons with less than maximum number ofnon-cumulative double bonds, for example where a saturated hydrocarbonring (such as a cyclopentyl ring) is fused with an aromatic ring (herein“aryl,” such as a benzene ring) to form, for example, groups such asindane.

As used herein, the term “cycloalkenyl” refers to an optionallysubstituted non-aromatic cyclic hydrocarbon ring containing one or morecarbon-to-carbon double bonds which optionally includes an alkylenelinker through which the cycloalkenyl may be attached, with multipledegrees of substitution included within the present invention. Exemplary“cycloalkenyl” groups include, but are not limited to, cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like,as well as substituted versions thereof.

As used herein, the term “heterocycle” or “heterocyclyl” refers to anoptionally substituted mono- or polycyclic ring system optionallycontaining one or more degrees of unsaturation and also containing oneor more heteroatoms. Preferred heteroatoms include N, O, and/or S,including N-oxides, sulfur oxides, and dioxides. Preferably the ring isthree to twelve-membered and is either fully saturated or has one ormore degrees of unsaturation. Multiple degrees of substitution areincluded within the present definition. Such rings may be optionallyfused to one or more of another “heterocyclic” ring(s) or cycloalkylring(s). Examples of “heterocyclic” groups include, but are not limitedto, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine,pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene.

The term “spirocyclyl,” as used herein, refers to an alkylene diradical,each end of which is attached to the same carbon atom of the parentmolecular moiety forming a bicyclic moiety.

As used herein, the term “alkoxy” refers to the group —OR^(a), whereR^(a) is alkyl as defined above.

As used herein, the phrase “optionally substituted” or variationsthereof denote an optional substitution, including multiple degrees ofsubstitution, with one or more substitutent group. Exemplary optionalsubstituent groups include acyl; alkyl; alkenyl; alkynyl; alkylsulfonyl;alkoxy; alkoxycarbonyl; cyano; halogen; haloalkyl; hydroxy; nitro; aryl,which may be further substituted with acyl, alkoxy, alkyl, alkenyl,alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro.

In certain embodiments, a compound of Formula I can include one or moreof bonds A-E, and hence one to four additional carbons, with theappropriate valencies. In certain embodiments, bonds B, C, and/or D areonly present when one or both of bonds A or E are present. For example,compounds of the invention can include, bond A, bonds A-B, bonds A-C,bonds A-D, bonds A-E, bonds B-E, bonds C-E, bonds D-E, bond D, or bondsA-B and D-E. In one embodiment, a compound of the invention includesbond E. In another embodiment, a compound of the invention includesbonds A-E. In a further embodiment, bonds A-D or B-E can form afive-membered ring.

Exemplary acridine and quinoline molecules of the instant compoundinclude, but are not limited to,

In addition to the above-disclosed molecules, it is contemplated thatthe one or more rings of acridine and quinoline molecules can bemodified with one or more heteroatoms to produce modifiedbisintercalators.

Compounds of Formula I can be prepared and purified using any othersuitable methodology routinely practiced in the art (see, Examples 1 and2), and be analyzed for their pharmacological properties by routinemethodologies. For example, kinetic solubility can be measured using adirect UV absorbance method or thermodynamic solubility can be measured.In addition, stability in gastrointestinal fluids can be determined byconventional methods (Asafu-Adjaye, et al. (2007) J. Pharm. Biomed.Anal. 43:1854-1859), e.g., 1 hour in simulated gastric fluid (pH 1.2,pepsin) at 37° C. and/or 3 hours in simulated intestinal fluid (pH 6.8,pancreatin). Furthermore, using the Parallel Artificial MembranePermeability Assay (PAMPA)-blood-brain barrier (BBB) permeability assay(Di, et al. (2009) J. Pharm. Sci. 98:1980-1991) or B—P dialysis (Kalvass& Maurer (2002) Biopharm. Drug Dispos. 23(8):327-38), brain penetrationcan be assessed. Furthermore, lipophilicity can be estimated bypartitioning between octanol and water using a shake flask method or pHmetric method and permeability can be assessed using the Caco-2 celllayer method of PAMPA assay.

Wherein R of Formula I is a tetrazole or CO₂H, an internal salt can beprepared. Alternative, pharmaceutically acceptable salts of the presentinvention can be prepared by conventional methods. Salts encompassedwithin the term “pharmaceutically acceptable salts” refer to non-toxicsalts of the compounds of this invention. Salts of the compounds of thepresent invention may include acid addition salts. In general, the saltsare formed from pharmaceutically acceptable inorganic and organic acids,or bases, as well as quaternary ammonium salts. More specific examplesof suitable acid salts include maleic, hydrochloric, hydrobromic,sulphuric, phosphoric, nitric, perchloric, fumic, acetic, propionic,succinic, glycolic, formic, lactic, aleic, tartaric, citric, palmoic,malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,fumaric, toluenesulfonic, methansulfonic (mesylate),naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic, hydroiodic,malic, teroic, tannic, and the like.

Other representative salts include acetate, benzenesulfonate, benzoate,besylate, bicarbonate, bisulfate, bitartrate, borate, bromide, calciumedetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylsulfate, monopotassium maleate, mucate, napsylate,nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, potassium,salicylate/disalicylate, sodium, stearate, subacetate, succinate,sulfate, tannate, tartrate, teoclate, tosylate, triethiodide,trimethylammonium, and valerate salts.

More specific examples of suitable basic salts include benzathine,sodium, lysine, lithium, potassium, magnesium, aluminum, calcium, zinc,N,N′-dibenzylethylenediamine, chloroprocaine, chlorine, diethanolamine,ethylenediamine, N-methylglucamine, and procaine salts.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound ofFormula I, or a salt thereof) and a solvent. Such solvents, for thepurpose of the invention, should not interfere with the biologicalactivity of the solute. Non-limiting examples of suitable solventsinclude, but are not limited to water, methanol, ethanol, and aceticacid. Preferably the solvent used is a pharmaceutically acceptablesolvent. Non-limiting examples of suitable pharmaceutically acceptablesolvents include water, ethanol, and acetic acid.

Processes for preparing pharmaceutically acceptable salts and solvatesof the compounds of Formula I are conventional in the art. See, forexample, Burger's Medicinal Chemistry and Drug Discovery, 5th Edition,Volume 1: Principles and Practice.

The DNA binding activity and efficacy of the compounds of this inventioncan be demonstrated using any convention method. For example, thermaldenaturation studies can be performed on calf thymus DNA (see, e.g.,Fiel, et al. (1979) Nucleic Acids Res. 6(9):3093-118; Nakaike, et al.(1992) Jpn. J. Cancer Res. 83(4):402-9; Fairley, et al. (1993) J. Med.Chem. 36(12):1746-53). In addition, the compounds can be analyzed fortheir ability to exhibit cytotoxicity in suitable cell line or animalmodels of cancer. For example, the murine leukemia cell line, L1210, isused in in vitro assays (Jaycox, et al. (1987) J. Heterocyclic. Chem.24:1405-1408), as well as in in vivo assays, wherein CD2F1 mice receiveL1210 leukemia cells by intraperitoneal injection (Edanami, et al.(1984) Cancer Chemother Pharmacol. 13(1):22-6; Douzono, et al. (1995)Jpn. J. Cancer Res. 86(3):315-21). Similarly, the human mammarycarcinoma MX-1 xenograft model is routinely used in the preclinicalanalysis of anti-tumor compounds in the treatment of breast cancer(Zhao, et al. (2008) Bioconjug Chem. 19(4):849-59; Wada, et al. (2007)Anticancer Res. 27:1431-5; Donawho, et al. (2007) Clin Cancer Res.13:2728-37). In this model, NU/NU Swiss (nude) mice receive anintrarenal inoculation of MX-1 cells prior to or after treatment withthe test compound. The human lung LX-1 xenograft model, wherein nudemice receive an intrarenal inoculation of LX-1 tumor cells, is alsoroutinely used in the preclinical analysis of anti-tumor compounds(Masuda, et al. (2006) J. Antibiot. (Tokyo) 59(4):209-14). Similarmodels exist for the analysis of anti-tumor activity in prostate cancer(e.g., the TRAMP model, wherein transgenic mice develop spontaneousprostate cancer), skin cancer (e.g., the Mouse B16 Melanoma model),ovarian cancer (mouse ovarian carcinoma xenograft model; Davis, et al.(1993) Cancer Research 53:2087-2091) and kidney cancer (e.g., the murinerenal cell carcinoma model (RENCA model)). Indeed, any suitable rodentor primate model can be used in the analysis of anti-tumor activity ofthe instant compounds. In each of these models, survival and/or tumorsize is measured and the results are expressed as the measurement madein the treated group divided by the measurement made in the vehicletreated control group. Results of this analysis are expected todemonstrate that tumor size is decreased and or survival is increased inanimals receiving treatment with a compound of the present invention.

Indeed, given the known antitumor activity bis-acridine or bis-quinolineintercalators, the compounds of the present invention find use in thetreatment of cancer. In addition, the compounds of the present inventionare contemplated as being more effective inhibitors of cancer cells thanthe anti-tumor bis-intercalators disclosed in the prior art because oftheir improved pharmacological properties. Accordingly, compounds of thepresent invention will be useful in treating subjects suffering fromcancer, such as leukemia, colon cancer, glioma (including astrocytomas,ependymal tumors, glioblastoma multiforme, and primitive neuroectodermaltumors), breast cancer, kidney cancer, lung cancer and the like. Indeed,it is contemplated that any cancer conventionally treated with ananti-tumor acridine or quinoline will likewise be treated with acompound of the present invention.

Accordingly, the present invention also provides methods for treatingcancer, wherein an effective amount of a compound of the presentinvention is administered to the subject in need of treatment so thatgrowth of the cancer cells is inhibited or decreased and the signs orsymptoms of the cancer are delayed, ameliorated, decreased or reversed.In this respect, “treatment” refers to both therapeutic treatment andprophylactic or preventative measures. As such, those in need oftreatment include those already with the disorder as well as those proneto have the disorder (e.g., by genetic predisposition or exposure tocarcinogenic agents). Subjects who can be treated in accordance with thepresent invention include mammals, such as humans, domestic and farmanimals, and zoo, sports, or pet animals, e.g., dogs, horses, cats,cows, etc. Preferably, the mammal herein is human.

For the purposes of the present invention, the term “effective amount”means that amount of a drug or pharmaceutical agent that will elicit thebiological or medical response of a tissue, system, animal, or humanthat is being sought, for instance, by a researcher or clinician. Foruse in therapy, effective amounts of a compound of Formula I, as well assalts or solvates thereof, may be administered as the raw chemical oroptionally presented as a pharmaceutical composition.

Accordingly, the invention further provides pharmaceutical compositions(also referred to herein as “pharmaceutical formulations”) that includeeffective amounts of compounds of the Formula I, or salts or solvatesthereof, and one or more pharmaceutically acceptable excipients(including carriers and/or diluents). The carrier(s), diluent(s) orexcipient(s) must be acceptable, in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient of the pharmaceutical composition. In preparing the instantpharmaceutical formulation, a compound of the Formula I, or a salt orsolvate thereof, is admixed with one or more pharmaceutically acceptablecarriers, diluents or excipients.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, as a non-limiting example, 0.5 mg to 1 g of acompound of the Formula I, depending on the compound, the conditionbeing treated, the route of administration, and the age, weight, andcondition of the patient. Preferred unit dosage formulations are thosecontaining a daily dose or sub-dose, as herein above recited, or anappropriate fraction thereof, of an active ingredient. Suchpharmaceutical formulations may be prepared by any of the methods wellknown in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by an oral (including buccal orsublingual), rectal, topical (including buccal, sublingual ortransdermal), vaginal, parenteral (including subcutaneous,intramuscular, intravenous or intradermal), by implantation, byintracavitary or intravesical instillation, intraocular, intraarterial,or intralesional route, or by application to mucous membranes, such as,that of the nose, throat, and/or bronchial tubes (i.e., inhalation).Such formulations may be prepared by any method known in the art ofpharmacy, for example by bringing into association the active ingredientwith the carrier(s) or excipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions, each with aqueous or non-aqueousliquids; edible foams or whips; or oil-in-water liquid emulsions orwater-in-oil liquid emulsions. For instance, for oral administration inthe form of a tablet or capsule, the active drug component can becombined with an oral, non-toxic pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Generally,powders are prepared by comminuting the compound to a suitable fine sizeand mixing with an appropriate pharmaceutical carrier such as an ediblecarbohydrate, as, for example, starch or mannitol. Flavorings,preservatives, dispersing agents, and coloring agents can also bepresent.

Capsules are made by preparing a powder, liquid, or suspension mixtureand encapsulating with gelatin or some other appropriate shell material.Glidants and lubricants such as colloidal silica, talc, magnesiumstearate, calcium stearate, or solid polyethylene glycol can be added tothe mixture before the encapsulation. A disintegrating or solubilizingagent such as agar-agar, calcium carbonate or sodium carbonate can alsobe added to improve the availability of the medicament when the capsuleis ingested. Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents, and coloring agents can also beincorporated into the mixture. Examples of suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth, orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, andthe like. Lubricants useful in these dosage forms include, for example,sodium oleate, sodium stearate, magnesium stearate, sodium benzoate,sodium acetate, sodium chloride, and the like. Disintegrators include,without limitation, starch, methyl cellulose, agar, bentonite, xanthangum, and the like.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant, andpressing into tablets. A powder mixture may be prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove. Optional ingredients include binders such ascarboxymethylcellulose, alginates, gelatins, or polyvinyl pyrrolidone,solution retardants such as paraffin, resorption accelerators such as aquaternary salt, and/or absorption agents such as bentonite, kaolin, ordicalcium phosphate. The powder mixture can be wet-granulated with abinder such as syrup, starch paste, acadia mucilage or solutions ofcellulosic or polymeric materials, and forcing through a screen. As analternative to granulating, the powder mixture can be run through thetablet machine and the result is imperfectly formed slugs broken intogranules. The granules can be lubricated to prevent sticking to thetablet-forming dies by means of the addition of stearic acid, a stearatesalt, talc or mineral oil. The lubricated mixture is then compressedinto tablets. The compounds of the present invention can also becombined with a free flowing inert carrier and compressed into tabletsdirectly without going through the granulating or slugging steps. Aclear or opaque protective coating consisting of a sealing coat ofshellac, a coating of sugar or polymeric material, and a polish coatingof wax can be provided. Dyestuffs can be added to these coatings todistinguish different unit dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared, for example, bydissolving the compound in a suitably flavored aqueous solution, whileelixirs are prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated generally by dispersing the compound in anon-toxic vehicle. Solubilizers and emulsifiers such as ethoxylatedisostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives;flavor additives such as peppermint oil, or natural sweeteners,saccharin, or other artificial sweeteners; and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds may also be coupled with soluble polymers as targetabledrug carriers. Such polymers can include polyvinylpyrrolidone (PVP),pyran copolymer, polyhydroxypropylmethacrylamide-phenol,polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug; for example, polylactic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations may be applied as a topical ointment orcream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles, and mouthwashes.

Pharmaceutical formulations adapted for nasal administration, where thecarrier is a solid, include a coarse powder having a particle size forexample in the range 20 to 500 microns. The powder is administered inthe manner in which snuff is taken, i.e., by rapid inhalation throughthe nasal passage from a container of the powder held close up to thenose. Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered dose pressurized aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and solutes that renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question. For example, formulationssuitable for oral administration may include flavoring or coloringagents.

The compounds of the present invention and their salts and solvatesthereof may be employed alone or in combination with other therapeuticagents. The compound(s) of Formula I and the other pharmaceuticallyactive agent(s) may be administered together or separately and, whenadministered separately, administration may occur simultaneously orsequentially, in any order. The amounts of the compound(s) of Formula Iand the other pharmaceutically active agent(s) and the relative timingsof administration will be selected in order to achieve the desiredcombined therapeutic effect.

The invention is described in greater detail by the followingnon-limiting examples.

Example 1 Synthesis of Bis-Acridine Having a ModifiedBis(4-Aminophenyl)Ether Tether

Example 2 Modifications to Bis-Acridine Intercalators

1-2. (canceled)
 3. A method for inhibiting growth of a cancer cellcomprising contacting a cancer cell with an effective amount of acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof,

wherein, dashed lines represent bonds that are independently present orabsent; and each R is independently an amide, amino, azido, nitro,hydroxyl, hydroxymethyl, carboxyl, cyano, sulfinyl, aryl, heteroaryl,alkenyl, alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycle,spirocycle, alkoxy, or halo group, so that growth of the cancer cell isinhibited.
 4. A method for treating cancer comprising administering to asubject in need of treatment an effective amount of a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of Formula I, or a pharmaceutically acceptable salt or solvatethereof,

wherein, dashed lines represent bonds that are independently present orabsent; and each R is independently an amide, amino, azido, nitro,hydroxyl, hydroxymethyl, carboxyl, cyano, sulfinyl, aryl, heteroaryl,alkenyl, alkyl, alkylene, cycloalkyl, cycloalkenyl, heterocycle,spirocycle, alkoxy, or halo group, thereby treating cancer in thesubject.